EP0526253B1 - 1,3-Oxathiolane nucleoside analogues - Google Patents

1,3-Oxathiolane nucleoside analogues Download PDF

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Publication number
EP0526253B1
EP0526253B1 EP92307051A EP92307051A EP0526253B1 EP 0526253 B1 EP0526253 B1 EP 0526253B1 EP 92307051 A EP92307051 A EP 92307051A EP 92307051 A EP92307051 A EP 92307051A EP 0526253 B1 EP0526253 B1 EP 0526253B1
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EP
European Patent Office
Prior art keywords
active ingredient
cis
therapeutic agent
hydroxymethyl
dideoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP92307051A
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German (de)
English (en)
French (fr)
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EP0526253A1 (en
Inventor
Gervais Dionne
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Shire Canada Inc
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Shire BioChem Inc
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Application filed by Shire BioChem Inc filed Critical Shire BioChem Inc
Priority to EP01119636A priority Critical patent/EP1155695B1/en
Publication of EP0526253A1 publication Critical patent/EP0526253A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
    • C12P17/167—Heterorings having sulfur atoms as ring heteroatoms, e.g. vitamin B1, thiamine nucleus and open chain analogs
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/26—Preparation of nitrogen-containing carbohydrates
    • C12P19/28—N-glycosides
    • C12P19/38—Nucleosides
    • C12P19/40—Nucleosides having a condensed ring system containing a six-membered ring having two nitrogen atoms in the same ring, e.g. purine nucleosides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/001—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by metabolizing one of the enantiomers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/006—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures

Definitions

  • the invention further provides the use of a mixture of (-)-cis-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl-(1H)-pyrimidin-2-one and (+)-cis-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one, or pharmaceutically acceptable derivatives thereof, wherein the (+) enantiomer is present in an amount less than about 5% w/w, for the manufacture of a medicament for the treatment of a mammal, including a human, suffering from or susceptible to viral infection comprising the rectal, nasal or vaginal administration or administration by inhalation or insufflation.
  • a pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, ester, or salt of such ester, of compound (A) or any other compound which, upon administration to the recipient is capable of providing (directly or indirectly) compound (A- or an antivirally active metabolite or residue thereof.
  • compound (A) may be modified to provide pharmaceutically acceptable derivatives thereof, at functional groups in both the base moiety and at the hydroxymethyl group of the oxathiolane ring. Modification at all such functional groups are included within the scope of the invention. However, of particular interest are pharmaceutically acceptable derivatives obtained by modification of the 2-hydroxymethyl group of the oxathiolane ring.
  • the compounds used according to the invention are also useful in the treatment of animals including man infected with the hepatitis B virus (HBV).
  • HBV hepatitis B virus
  • the compounds used according to the invention are also useful in the treatment of AIDS related conditions such as AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), AIDS-related neurological conditions (such a dementia or tropical paraparesis), anti-HIV antibody positive and HIV-positive conditions.
  • AIDS related conditions such as AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), AIDS-related neurological conditions (such a dementia or tropical paraparesis), anti-HIV antibody positive and HIV-positive conditions.
  • ARC AIDS-related complex
  • PDL progressive generalized lymphadenopathy
  • AIDS-related neurological conditions such a dementia or tropical paraparesis
  • anti-HIV antibody positive and HIV-positive conditions such as AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), AIDS-related neurological conditions (such a dementia or tropical paraparesis), anti-HIV antibody positive and HIV-positive conditions.
  • Kaposi's sarcoma thrombocytopenia purpurea and
  • the desired dose' may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 1 to about 75 ⁇ M, preferably about 2 to 50 ⁇ M, most preferably about 3 to about 30 ⁇ M. This may be achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1 to about 100 mg of the active ingredient. Desirable blood levels may be maintained by a continuous infusion to provide about 0.01 to about 5.0 mg/kg/hour or by intermittent infusions containing about 0.4 to about 15 mg/kg of the active ingredient.
  • the compounds according to the invention are conveniently delivered from an insufflator, nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form in, for example, capsules or cartridges or e.g., gelatin or blister packs from which the powder may be administered with the aid of. an inhalator or insufflator.
  • Suitable therapeutic agents for use in such combinations include acyclic nucleosides such as acyclovir or ganciclovir, interferons such as alpha, beta or gamma-interferon, renal excretion inhibitors such as probenecid, nucleoside transport inhibitors such as dipyridamole, 2',3'-dideoxynucleosides such as AZT, 2',3'-dideoxycytidine, 2',3'-dideoxyadenosine, 2',3'-dideoxyinosine, 2',3'-dideoxythymidine, 2',3'-dideoxy-2',3'-didehydrothymidine and 2',3'-dideoxy-2',3'-didehydrocytidine, immunomodulators such as interleukin-2 (IL-2) and granulocyte macrophage colony stimulating factor (GM-CSF), erythropoietin, ampligen, th
  • each compound may be either the same as or differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
  • a 1,3-oxathiolane of formula (VIII) wherein the anomeric group L is a displaceable group is reacted with an appropriate base.
  • Suitable groups L include -OR where R is an alkyl group, e.g., a C 1-6 alkyl group such as methyl or R is an acyl group, e.g., a C 1-6 alkyl group such as acetyl or halogen, for example iodine, bromine or chlorine.
  • the 1,3-oxathiolanes of formula (VIII) may be prepared for example by reaction of an aldehyde of formula (VII) with a mercaptoacetal of formula (VI) in a compatible organic solvent, such as toluene in the presence of an acid catalyst for example a Lewis acid such as zinc chloride.
  • a compatible organic solvent such as toluene
  • an acid catalyst for example a Lewis acid such as zinc chloride.
  • the aldehydes of formula (VII) may be prepared by methods known in the art for example E.G. Halloquist and H. Hibbert, Can. J. Research, 8, pp. 129-136 (1933). Conveniently the crude aldehyde (VII) may be purified by conversion to the crystalline bisulphite addition adduct and subsequent reconversion to the free aldehyde.
  • alkyl, silyl, acyl and heterocyclic groups may be removed by solvolysis, e.g., by hydrolysis under acidic or basic conditions.
  • Aralkyl groups such as triphenylmethyl may similarly be removed by solvolysis, e.g., by hydrolysis under acidic conditions.
  • Aralkyl groups such as benzyl may be cleaved for example by treatment with BF 3 /etherate and acetic anhydride followed by removal of acetate groups so formed at an appropriate stage in the synthesis.
  • Silyl groups may also conveniently be removed using a source of fluoride ions such as tetra-n-butylammonium fluoride.
  • Resolution of the final product, or an intermediate or starting material therefor may be effected by any suitable method known in the art: see for example E.L. Eliel, Stereochemistry of Carbon Compounds , McGraw Hill (1962) and S.H. Wilen, Tables of Resolving Agents.
  • the compound (A) may be obtained by chiral HPLC using a suitable stationary phase for example acetylated ⁇ -cyclodextrin or cellulose triacetate and a suitable solvent for example an alcohol such as ethanol or an aqueous solution of for example triethyl ammonium acetate.
  • a suitable stationary phase for example acetylated ⁇ -cyclodextrin or cellulose triacetate and a suitable solvent for example an alcohol such as ethanol or an aqueous solution of for example triethyl ammonium acetate.
  • the compounds may be resolved by enzyme mediated enantioselective catabolism with a suitable enzyme such as cytidine deaminase or selective enzymatic degradation of a suitable derivative a 5'-nucleotidase.
  • the enzyme may be employed either in solution or, more conveniently, in immobilized form. Enzymes may be immobilized by any method known in the art, for example by adsorption onto

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biochemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Virology (AREA)
  • Analytical Chemistry (AREA)
  • Molecular Biology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Epidemiology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • AIDS & HIV (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Saccharide Compounds (AREA)
  • Medicinal Preparation (AREA)
EP92307051A 1991-08-01 1992-08-03 1,3-Oxathiolane nucleoside analogues Expired - Lifetime EP0526253B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP01119636A EP1155695B1 (en) 1991-08-01 1992-08-03 Use of a 1,3 oxathiolane nucleoside analogue in the manufacture of a medicament for specific administration

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB919116601A GB9116601D0 (en) 1991-08-01 1991-08-01 1,3-oxathiolane nucleoside analogues
GB9116601 1991-08-01

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP01119636A Division EP1155695B1 (en) 1991-08-01 1992-08-03 Use of a 1,3 oxathiolane nucleoside analogue in the manufacture of a medicament for specific administration

Publications (2)

Publication Number Publication Date
EP0526253A1 EP0526253A1 (en) 1993-02-03
EP0526253B1 true EP0526253B1 (en) 2002-11-13

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ID=10699340

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EP01119636A Expired - Lifetime EP1155695B1 (en) 1991-08-01 1992-08-03 Use of a 1,3 oxathiolane nucleoside analogue in the manufacture of a medicament for specific administration
EP92307051A Expired - Lifetime EP0526253B1 (en) 1991-08-01 1992-08-03 1,3-Oxathiolane nucleoside analogues

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Country Status (41)

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US (2) US5538975A (ru)
EP (2) EP1155695B1 (ru)
JP (1) JP2960778B2 (ru)
KR (1) KR100242454B1 (ru)
CN (5) CN1034810C (ru)
AP (1) AP321A (ru)
AT (2) ATE448787T1 (ru)
AU (1) AU659668B2 (ru)
BG (1) BG61693B1 (ru)
CA (2) CA2114221C (ru)
CZ (1) CZ283765B6 (ru)
DE (2) DE69232845T2 (ru)
DK (2) DK0526253T3 (ru)
EE (1) EE03002B1 (ru)
EG (1) EG20193A (ru)
ES (2) ES2335968T3 (ru)
FI (1) FI940435A0 (ru)
GB (1) GB9116601D0 (ru)
GE (1) GEP20002094B (ru)
HK (2) HK1008672A1 (ru)
HN (1) HN1997000118A (ru)
HU (2) HUT70030A (ru)
IL (1) IL102616A (ru)
MA (1) MA22919A1 (ru)
MD (1) MD1434C2 (ru)
MX (1) MX9204474A (ru)
NO (3) NO300842B1 (ru)
NZ (1) NZ243637A (ru)
OA (1) OA09883A (ru)
PH (1) PH30983A (ru)
PT (2) PT526253E (ru)
RS (1) RS49993B (ru)
RU (1) RU2126405C1 (ru)
SG (1) SG68541A1 (ru)
SK (1) SK280131B6 (ru)
TJ (1) TJ244R3 (ru)
TN (1) TNSN92070A1 (ru)
TW (2) TW366347B (ru)
WO (1) WO1993003027A1 (ru)
YU (1) YU49259B (ru)
ZA (1) ZA925668B (ru)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11116737B1 (en) 2020-04-10 2021-09-14 University Of Georgia Research Foundation, Inc. Methods of using probenecid for treatment of coronavirus infections

Families Citing this family (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6903224B2 (en) 1988-04-11 2005-06-07 Biochem Pharma Inc. Substituted 1,3-oxathiolanes
US6069252A (en) * 1990-02-01 2000-05-30 Emory University Method of resolution and antiviral activity of 1,3-oxathiolane nucleoside enantiomers
US5276151A (en) * 1990-02-01 1994-01-04 Emory University Method of synthesis of 1,3-dioxolane nucleosides
US6703396B1 (en) 1990-02-01 2004-03-09 Emory University Method of resolution and antiviral activity of 1,3-oxathiolane nuclesoside enantiomers
US5914331A (en) * 1990-02-01 1999-06-22 Emory University Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane
US5204466A (en) * 1990-02-01 1993-04-20 Emory University Method and compositions for the synthesis of bch-189 and related compounds
US5444063A (en) * 1990-12-05 1995-08-22 Emory University Enantiomerically pure β-D-dioxolane nucleosides with selective anti-Hepatitis B virus activity
US5925643A (en) * 1990-12-05 1999-07-20 Emory University Enantiomerically pure β-D-dioxolane-nucleosides
US6812233B1 (en) * 1991-03-06 2004-11-02 Emory University Therapeutic nucleosides
US5817667A (en) * 1991-04-17 1998-10-06 University Of Georgia Research Foudation Compounds and methods for the treatment of cancer
GB9116601D0 (en) * 1991-08-01 1991-09-18 Iaf Biochem Int 1,3-oxathiolane nucleoside analogues
GB9226927D0 (en) * 1992-12-24 1993-02-17 Iaf Biochem Int Dideoxy nucleoside analogues
GB9311709D0 (en) * 1993-06-07 1993-07-21 Iaf Biochem Int Stereoselective synthesis of nucleoside analogues using bicycle intermediate
US20020120130A1 (en) 1993-09-10 2002-08-29 Gilles Gosselin 2' or 3' -deoxy and 2', 3' -dideoxy-beta-L-pentofuranonucleo-side compounds, method of preparation and application in therapy, especially as anti- viral agents
WO1995007086A1 (en) * 1993-09-10 1995-03-16 Emory University Nucleosides with anti-hepatitis b virus activity
US5587362A (en) * 1994-01-28 1996-12-24 Univ. Of Ga Research Foundation L-nucleosides
IL113432A (en) 1994-04-23 2000-11-21 Glaxo Group Ltd Process for the diastereoselective synthesis of nucleoside analogues
IL115156A (en) 1994-09-06 2000-07-16 Univ Georgia Pharmaceutical compositions for the treatment of cancer comprising 1-(2-hydroxymethyl-1,3-dioxolan-4-yl) cytosines
US6391859B1 (en) 1995-01-27 2002-05-21 Emory University [5-Carboxamido or 5-fluoro]-[2′,3′-unsaturated or 3′-modified]-pyrimidine nucleosides
US5703058A (en) * 1995-01-27 1997-12-30 Emory University Compositions containing 5-fluoro-2',3'-didehydro-2',3'-dideoxycytidine or a mono-, di-, or triphosphate thereof and a second antiviral agent
US5808040A (en) * 1995-01-30 1998-09-15 Yale University L-nucleosides incorporated into polymeric structure for stabilization of oligonucleotides
GB9506644D0 (en) * 1995-03-31 1995-05-24 Wellcome Found Preparation of nucleoside analogues
AU722214B2 (en) 1995-06-07 2000-07-27 Centre National De La Recherche Scientifique (Cnrs) Nucleosides with anti-hepatitis B virus activity
US5753789A (en) * 1996-07-26 1998-05-19 Yale University Oligonucleotides containing L-nucleosides
US6071922A (en) 1997-03-19 2000-06-06 Emory University Synthesis, anti-human immunodeficiency virus, and anti-hepatitis B virus activities of 1,3-oxaselenolane nucleosides
JP2001518899A (ja) 1997-04-07 2001-10-16 トライアングル ファーマシューティカルズ，インコーポレイティド 他の抗ウイルス剤との組合せにおけるｍｋｃ−４４２の使用
RU2439069C2 (ru) 1998-08-12 2012-01-10 Гайлид Сайенсиз, Инк. Способ получения 1,3-оксатиолановых нуклеозидов
US6979561B1 (en) 1998-10-09 2005-12-27 Gilead Sciences, Inc. Non-homogeneous systems for the resolution of enantiomeric mixtures
ATE287268T1 (de) 1998-11-02 2005-02-15 Gilead Sciences Inc Kombinationstherapie zur behandlung von hepatitis b infektionen
US6436948B1 (en) 2000-03-03 2002-08-20 University Of Georgia Research Foundation Inc. Method for the treatment of psoriasis and genital warts
ATE339211T1 (de) 2000-03-29 2006-10-15 Univ Georgetown L-fmau zur behandlung von hepatitis-delta-virus- infizierung
CA2308559C (en) 2000-05-16 2005-07-26 Brantford Chemicals Inc. 1,3-oxathiolan-5-ones useful in the production of antiviral nucleoside analogues
CA2690137C (en) * 2001-03-01 2012-11-13 Gilead Sciences, Inc. Polymorphic and other crystalline forms of cis-ftc
AU2008202336B2 (en) * 2001-03-01 2011-11-10 Abbvie Inc. Polymorphic and other crystalline forms of cis-FTC
WO2003051298A2 (en) * 2001-12-14 2003-06-26 Pharmasset Ltd. Preparation of intermediates useful in the synthesis of antiviral nucleosides
ATE398455T1 (de) 2003-01-14 2008-07-15 Gilead Sciences Inc Zusammensetzungen und verfahren zur antiviralen kombinationstherapie
ITMI20030578A1 (it) * 2003-03-24 2004-09-25 Clariant Lsm Italia Spa Processo ed intermedi per la preparazione di emtricitabina
TWI471145B (zh) 2005-06-13 2015-02-01 Bristol Myers Squibb & Gilead Sciences Llc 單一式藥學劑量型
TWI375560B (en) 2005-06-13 2012-11-01 Gilead Sciences Inc Composition comprising dry granulated emtricitabine and tenofovir df and method for making the same
CN100360528C (zh) * 2005-08-31 2008-01-09 四川大学 4-氨基-1-(2-羟甲基-1,3-氧硫杂环戊烷-5-基)-2(1h)-嘧啶酮的制备方法
WO2007077505A2 (en) * 2005-12-30 2007-07-12 Ranbaxy Laboratories Limited Crystalline l-menthyl (2r, 5s)-5-(4-amino-5-fluoro-2-oxo-2h-pyrimidin-1-yl)[1, 3]oxathiolan-2-carboxylate and process for preparation thereof
US8173621B2 (en) 2008-06-11 2012-05-08 Gilead Pharmasset Llc Nucleoside cyclicphosphates
SG172363A1 (en) 2008-12-23 2011-07-28 Pharmasset Inc Synthesis of purine nucleosides
WO2010075517A2 (en) * 2008-12-23 2010-07-01 Pharmasset, Inc. Nucleoside analogs
CL2009002207A1 (es) 2008-12-23 2011-02-18 Gilead Pharmasset Llc Compuestos derivados de 3-hidroxi-5-(9h-purin-9-il)tetrahidrofuran-2-il, inhibidor de la replicacion de arn viral dependiente de arn; composicion farmaceutica; uso para el tratamiento de hepatitis c.
CN102482639B (zh) 2009-04-03 2016-01-06 医学研究会 活化诱导胞苷脱氨酶(aid)突变体及使用方法
EP2377862A1 (en) 2010-03-29 2011-10-19 Esteve Química, S.A. Process for obtaining emtricitabine
AP3515A (en) 2010-03-31 2016-01-11 Gilead Pharmasset Llc Nucleoside phosphoramidates
AU2012365627B2 (en) 2012-01-10 2017-05-25 C.C.Jensen A/S Method and system for cleaning degraded oil

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5668674A (en) * 1979-11-08 1981-06-09 Shionogi & Co Ltd 5-fluorouracil derivative
DE2950317A1 (de) * 1979-12-14 1981-06-19 Agfa-Gevaert Ag, 5090 Leverkusen Elektrothermographische vorrichtung
US5466806A (en) * 1989-02-08 1995-11-14 Biochem Pharma Inc. Processes for preparing substituted 1,3-oxathiolanes with antiviral properties
US5270315A (en) * 1988-04-11 1993-12-14 Biochem Pharma Inc. 4-(purinyl bases)-substituted-1,3-dioxlanes
US5047407A (en) * 1989-02-08 1991-09-10 Iaf Biochem International, Inc. 2-substituted-5-substituted-1,3-oxathiolanes with antiviral properties
PT674634E (pt) * 1989-02-08 2003-09-30 Iaf Biochem Int Processos para preparar 1,3-oxatiolanos substituidos com propriedades antivirais
US5276151A (en) * 1990-02-01 1994-01-04 Emory University Method of synthesis of 1,3-dioxolane nucleosides
US5204466A (en) * 1990-02-01 1993-04-20 Emory University Method and compositions for the synthesis of bch-189 and related compounds
GB9009861D0 (en) * 1990-05-02 1990-06-27 Glaxo Group Ltd Chemical compounds
US5248776A (en) * 1990-12-05 1993-09-28 University Of Georgia Research Foundation, Inc. Process for enantiomerically pure β-L-1,3-oxathiolane nucleosides
WO1992010496A1 (en) * 1990-12-05 1992-06-25 University Of Georgia Research Foundation, Inc. ENANTIOMERICALLY PURE β-L-(-)-1,3-OXATHIOLANE NUCLEOSIDES
US5444063A (en) * 1990-12-05 1995-08-22 Emory University Enantiomerically pure β-D-dioxolane nucleosides with selective anti-Hepatitis B virus activity
NZ241625A (en) * 1991-02-22 1996-03-26 Univ Emory 1,3-oxathiolane derivatives, anti-viral compositions containing such and method of resolving racemic mixture of enantiomers
DE69233693T2 (de) * 1991-03-06 2008-01-24 Emory University Salze und Amide von (-) cis 5-Fluoro-2'-deoxy-3'-thiacytidine geeignet für die Behandlung von Hepatitis B
GB9104740D0 (en) * 1991-03-06 1991-04-17 Wellcome Found Antiviral nucleoside combination
WO1992018517A1 (en) * 1991-04-17 1992-10-29 Yale University Method of treating or preventing hepatitis b virus
GB9111902D0 (en) * 1991-06-03 1991-07-24 Glaxo Group Ltd Chemical compounds
GB9116601D0 (en) * 1991-08-01 1991-09-18 Iaf Biochem Int 1,3-oxathiolane nucleoside analogues

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11116737B1 (en) 2020-04-10 2021-09-14 University Of Georgia Research Foundation, Inc. Methods of using probenecid for treatment of coronavirus infections
US11903916B2 (en) 2020-04-10 2024-02-20 University Of Georgia Research Foundation, Inc. Methods of using probenecid for treatment of coronavirus infections

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